Red Blood Cell Transfusion Pocket Guide

166
Guidance for Industry
ENVIRONMENTAL IMPACT ASSESSMENTS (EIA’s) FOR

VETERINARY MEDICINAL PRODUCTS (VMP’s) - PHASE II
VICH GL38
FINAL GUIDANCE
This VICH guidance document provides guidance for the use of a single set of environmental fate
and toxicity data to be used by applicants/sponsors to obtain marketing approval in all VICH
regions for those veterinary medicinal products (VMP’s) identified as recommending data during
the Phase I process.
Comments and suggestions regarding the document should be submitted to Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852. Submit electronic comments to http://www.regulations.gov/. All comments should be
identified with the Docket No. 2004D-0156.
For questions regarding this document: Charles E. Eirkson, Center for Veterinary Medicine, (HFV-
103), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 240-276-8173, e-
mail: charles.eirkson@fda.hhs.gov.
U.S. Department of Health and Human Services

Food and Drug Administration
Center for Veterinary Medicine
January 9, 2006
Contains Non-Binding Recommendation
VICH GL 38 (ECOTOXICITY PHASE II)

October 2004
For implementation at Step 7
E NVIRONMENTAL I MPACT A SSESSMENT FOR

V ETERINARY M EDICINAL P RODUCTS
P HASE II G UIDANCE
Recommended for Adoption

at Step 7 of the VICH Process
in October 2004 by the VICH SC for implementation in October 2005
This Guidance has been developed by the appropriate VICH Expert Working Group and is subject
to consultation by the parties, in accordance with the VICH Process. At Step 7 of the Process the
final draft was recommended for adoption to the regulatory bodies of the European Union, Japan
and USA.
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VICH-GL38
ENVIRONMENTAL IMPACT ASSESSMENT FOR
VETERINARY MEDICINAL PRODUCTS
PHASE II GUIDANCE
TABLE OF CONTENTS
1 INTRODUCTION ............................................................................................................ 7
1.1....... Purpose of this Guidance Document..............................................................7
1.2....... Scope ..............................................................................................................8
2 GENERAL ELEMENTS ........................................................................................ 8
2.1....... Protection Goals .............................................................................................8
2.2....... General Description and Use of Phase II .......................................................8
2.3....... Exposure of VMPs to the Environment .........................................................9
2.4....... Risk Quotient (RQ) Approach .......................................................................9
2.5....... Test Guidelines ............................................................................................10
2.6....... Metabolites ...................................................................................................10
2.7....... Special Consideration for Biodegradation Data...........................................11
3 RECOMMENDED STUDIES AT TIER A AND TIER B .................................. 11
3.1....... Tier A Testing ..............................................................................................11
3.1.2 ...... Tier A Environmental Fate Studies .........................................................12
3.1.3 ...... Tier A Effects Testing .............................................................................12
3.1.3.1 Tier A Aquatic Effects Studies ................................................................. 12
3.1.3.2 Tier A Terrestrial Effects Studies ............................................................. 13
3.1.4 ...... Risk assessment at Tier A .......................................................................14
3.1.4.1 PEC refinement......................................................................................... 14
3.2....... Criteria for Tier B Testing ...........................................................................15
3.3....... Tier B Testing ..............................................................................................15
3.3.1 ...... Tier B Physical-Chemical Properties Studies .........................................15
3.3.2 ...... Tier B Environmental Fate Studies .........................................................15
3.3.3 ...... Tier B Environmental Effects Studies.....................................................15
3.3.3.1 Tier B Aquatic effects studies .................................................................. 15
3.3.3.2 Tier B Terrestrial effects studies .............................................................. 16
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4 AQUACULTURE BRANCH ............................................................................... 17

4.1....... Introduction ..................................................................................................17
4.2....... Tier A ...........................................................................................................18
4.2.1 ...... Data recommended in Tier A ..................................................................18
4.2.1.1 Physical-chemical properties studies ........................................................ 18
4.2.1.2 Environmental fate studies ....................................................................... 18
4.2.1.3 Environmental effects studies................................................................... 18
4.2.2 ...... Calculation and comparison of PEC surfacewater .........................................18
4.2.2.1 Calculation of PEC surfacewater-initial (PEC sw-initial ) ......................................... 18
4.2.2.2 Comparison of PNEC and PEC sw-initial ..................................................... 19
4.2.2.3 Calculation of PEC sw-refined ....................................................................... 19
4.2.3 ...... Calculation and comparison of PEC sediment .............................................19
4.2.3.1 Calculation of PEC sediment ......................................................................... 19
4.2.3.2 Calculation of PEC sediment in cases of VMPs added to feed ..................... 19
4.2.3.3. Comparison of PNEC and PEC ................................................................... 20
4.3....... Tier B ...........................................................................................................20
4.3.1 ...... Triggers for testing in Tier B ..................................................................20
4.3.2 ...... Data recommended in Tier B ..................................................................20
4.3.3 ...... Further assessment ..................................................................................20
5 INTENSIVELY REARED ANIMALS BRANCH............................................... 22
5.1....... Introduction ..................................................................................................22
5.2....... Tier A ...........................................................................................................22
5.2.2 ...... Calculation and comparison of PEC soil ...................................................23
5.2.2.1 Calculation of PEC soil-initial ........................................................................ 23
5.2.2.2 Comparison of PNEC and PEC soil-initial ..................................................... 23
5.2.2.3 Calculation of PEC soil-refined ...................................................................... 23
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5.2.3 ...... Calculation and comparison of PEC water .............................................24

5.2.3.1 Calculation and comparison of PEC sw-initial .............................................. 24
5.2.3.2 Calculation of PEC groundwater ..................................................................... 24
5.3....... Tier B ...........................................................................................................24
5.3.1 ...... Triggers for further testing in Tier B.......................................................24
5.3.2 ...... Data recommended in Tier B ..................................................................24
6 PASTURE ANIMALS BRANCH ........................................................................ 27
6.1....... Introduction ..................................................................................................27
6.2....... Tier A ...........................................................................................................27
6.2.2 ...... Calculation and comparison of PEC soil ...................................................28
6.2.2.1 Calculation of PEC soil-initial ........................................................................ 28
6.2.2.2 Comparison of PNEC with PEC soil-initial ................................................... 28
6.2.2.3 Calculation of PEC soil-refined ...................................................................... 28
6.2.3 ...... Calculation and comparison of PEC dung ..................................................29
6.2.3.1 Calculation of PEC dung-initial ...................................................................... 29
6.2.3.2 Comparison of PNEC with PEC dung-initial .................................................. 29
6.2.3.3 Calculation of PEC dung-refined ..................................................................... 29
6.2.4 ...... Calculation and comparison of PEC water .............................................29
6.2.4.1 Surface water and groundwater ................................................................ 29
6.2.4.2 Aquatic Exposure Scenarios ..................................................................... 29
6.2.4.3 Comparison of PNEC with PEC sw-initial .................................................... 31
6.2.4.4 Calculation of PEC sw-initial-refined ................................................................ 31
6.3....... Tier B ...........................................................................................................31
6.3.1 ...... Triggers for further testing in Tier B.......................................................31
6.3.2 ...... Data recommended for Tier B.................................................................31
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7 GLOSSARY (Definitions of Terms) .................................................................... 34
8 OECD/ISO TEST Guidelines for recommended studies ...................................... 35
Section 1 – OECD Physical-Chemical Properties ....................................................35
Section 2 – OECD Effects on Biotic Systems ..........................................................36
Section 3 – OECD Degradation and Accumulation..................................................36
Section 4 – ISO Guidelines .......................................................................................37
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ENVIRONMENTAL IMPACT ASSESSMENT FOR VETERINARY

MEDICINAL PRODUCTS - PHASE II
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on the subject matter. It does
not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want
to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
1 INTRODUCTION
1.1 Purpose of this Guidance Document

The purpose of this document is to provide guidance for the use of a single set of environmental fate
and toxicity data to be used by applicants/sponsors to obtain marketing approval in all VICH
regions for those veterinary medicinal products (VMPs) identified as recommending data during the
Phase I process. It also aims to be a major contribution towards the common use of study methods
used to generate these data.
It needs to be kept in mind that guidances should not consist of rigid stipulations, but should make
clear recommendations on the minimum information needed. By their nature, guidances address
most, but not all possible eventualities. Each case has to be considered on its merits, and if in a
particular circumstance an alternative approach, for example use of data published in the literature,
is deemed more fitting, a reasoned argument for the deviation should be prepared and discussed
with appropriate regulatory authorities before work is initiated.
Besides serving as a common basis for the Environmental Impact Assessment (EIA), this document
provides recommendations to protect the environment. The field of ecotoxicology is a complex
science and gaps in data and knowledge exist. Notwithstanding these limitations, the Phase II
recommendations should be based on science and strive for objectivity. The maximum amount of
information should be extracted from each study to achieve an understanding of the potential for a
given VMP to affect the environment.
An important factor in the use of the guidance contained herein is professional judgement. Expertise
in the appropriate scientific disciplines is a valuable prerequisite for designing an EIA program for
VMPs. Such expertise is important in evaluating the relevance of available data, for predicting
environmental exposures, for identifying the recommended studies, and interpreting exposures
relative to endpoint values obtained in such studies.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word “should” in Agency guidances means that
something is suggested or recommended, but not required.
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1.2 Scope
The mandate given by the VICH Steering Committee for developing this guidance is described in
the Phase I document (http://www.vichsec.org/pdf/2000/Gl06_st7.pdf,
http://fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustr
y/UCM052424.pdf).
The scope of the guidance is for VMPs, as defined by the individual parties to VICH. Particular
VICH regions may mandate legislatively that this guidance be applicable to new products only or to
both new and old products. Therefore, it is incumbent upon the applicant/sponsor to determine what
the case is for a particular VMP. If an applicant/sponsor uses an alternative approach to conducting
an EIA, then they should assess the suitability of the deviation from the guidance contained herein
with the appropriate regulatory authority. However, an alternative approach, depending on the
nature of the deviation from the guidance and the justification for it, may result in a submission not
being accepted by all parties to VICH.
2 GENERAL ELEMENTS
Phase II provides a common basis for EIA testing for VMPs between the EU, Japan, US, Canada
and Australia/New Zealand. It is recognized that significant regional differences (e.g. animal
husbandry practices, climates, soil and water types, etc.) preclude fully harmonized guidance at this
time. Full harmonization on principles of fate, effects and risk assessment is possible; the
parameterization and decision making is, however, the prerogative of the individual regulatory
authority. For this reason, the scope and extent of information recommended for EIAs for all
regions cannot be completely specified. To the extent possible, Phase II provides recommendations
for standard datasets and conditions for determining whether more information should be generated
for a given VMP.
2.1 Protection Goals

Legislation and policy on environmental quality in the VICH regions set out the protection goals
reflected in the EIA. The overall target of the assessment is the protection of ecosystems.
The aim of the guidance provided in Phase II (and in Phase I) is to assess the potential for VMPs to
affect non-target species in the environment, including both aquatic and terrestrial species. It is not
possible to evaluate the effects of VMPs on every species in the environment that may be exposed
to the VMP following its administration to the target species. The taxonomic levels tested are
intended to serve as surrogates or indicators for the range of species present in the environment.
Impacts of greatest potential concern are usually those at community and ecosystem function levels,
with the aim being to protect most species. However, it may be important to distinguish between
local and landscape effects. There may be some instances where the impact of a VMP at a single
location may be of significant concern, for example, for endangered species or a species with key
ecosystem functions. These issues should be handled by risk management at that specific location,
which may even include restriction or prohibition of use of the product of concern in that specific
local area. Additionally, issues associated with cumulative impact of some VMPs may be
appropriate at a landscape level. These types of issues cannot be harmonized but should be
considered as part of the EIA and if recommended, addressed by each region/local area.
2.2 General Description and Use of Phase II

This Phase II guidance contains sections for each of the major branches: (1) aquaculture, (2)
intensively reared terrestrial animals and (3) pasture animals, each containing decision trees
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pertaining to the branch. The document also contains a section listing the recommended studies for
physical/chemical properties, environmental fate and environmental effects, as well as a description
of how to determine when studies may be relevant.
The guidance uses a two-tiered approach to the environmental risk assessment. The first tier, Tier
A, makes use of simpler, less expensive studies to produce a conservative assessment of risk based
on exposure and effects in the environmental compartment of concern. If the EIA cannot be
completed with such data, due to a prediction of unacceptable risk, then the applicant/sponsor
progresses to Tier B to refine the EIA.
In some cases, it may be possible to implement a risk management option instead of moving to Tier
B. In these cases, discussion with the regulatory authority is recommended. It should be
recognized that risk management may not be identical for all regions and where Tier B testing is
omitted in one region, it may still be recommended in another.
For certain VMPs, it may be recommended to go beyond Tier B because more complex studies,
specific to issues being addressed or to a particular region, are recommended to complete the risk
assessment. Such studies cannot be comprehensively dealt with in a harmonized guidance
document. Therefore, these issues do not fall within the purview of this document, but should be
addressed on a case-by-case basis with the appropriate regulatory authority. Examples include
exceeding relevant trigger values in Tier B, where further testing may be warranted and/or risk
mitigation measures may be recommended. As risk management measures are not within the scope
of this guidance document, no guidance on these aspects is possible.
2.3 Exposure of VMPs to the Environment

The route and quantity of a VMP entering the environment determines the risk assessment scenarios
that are applicable and the extent of the risk assessment. This guidance sets out a number of
emission scenarios, using various assumptions. There may be some emission scenarios that are not
applicable to a specific region. Emission can occur at various stages in the life cycle of the product.
However, with the exception of certain topicals or those added directly to water, most VMPs first
pass through the animal to which it is administered. Generally the most significant environmental
exposure results from excretion of the active substance being the parent and/or its metabolites.
Following excretion, residues are generally assumed to be uniformly distributed in the environment;
even though distribution may be patchy.
2.4 Risk Quotient (RQ) Approach

The EIA is based on the accepted principle that risk is a product of the exposure, fate and effects
assessments of the VMP for the environmental compartments of concern. The Phase II EIA is
based on a RQ approach, which is the ratio of the predicted environmental concentration (PEC) and
the predicted no effect concentration (PNEC) on non-target organisms. The RQ (PEC/PNEC) is
compared against a value of one, and a value less than one indicates that no further testing is
recommended. However, in some circumstances, professional judgement is needed for a final
determination.
The PEC of the RQ is defined as the concentration of the parent compound and metabolites
predicted to be present in the soil, water and sediment compartment. Worldwide harmonization of
PEC calculations is not practical or possible at this time. Regional differences in animal husbandry
practices, different environmental conditions in the VICH regions, differences in treatment rates and
frequency, should be taken into account when calculating PECs. Therefore this document does not
contain any examples of PEC calculations but gives some general qualitative guidance needed to
determine PECs. It is incumbent upon the applicant/sponsor to determine the most appropriate
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method of estimating exposures for the region of interest for a particular VMP based on regulatory
guidance.
The PNEC of the RQ is determined from the experimentally determined effects endpoint divided by
an appropriate assessment factor (AF). The AF is intended to cover uncertainties such as intra- and
inter-laboratory and species variation, the need to extrapolate from laboratory study results to the
field, and from short term to long term toxicity (acute:chronic ratios). The value varies depending
on the type of study conducted. Variation in the AF applied should be clearly justified in the
submission.
AFs of between 1000 and 10 are used in the assessment. A factor of 1000 is designed to be
conservative and protective and is applied when only limited data are available; this value may be
progressively reduced to 10 as more evidence becomes available. Such evidence could include:
(1) availability of data from a wide variety of species including those which are considered
to represent the most sensitive species.
(2) information from structurally similar compounds, to suggest that the acute to chronic
ratio is likely to be lower than that for many other compounds; and
(3) information to suggest that the chemical is rapidly degraded and not repeatedly
administered so as to lead to chronic exposure.
2.5 Test Guidelines

The specific test guidelines/protocols recommended in Phase II are those finalized by OECD/ISO.
This has the advantage of ensuring that environmental studies are current and broadly acceptable to
regulatory authorities on a worldwide basis. Lack of a specific study recommendation, however,
does not eliminate the importance for data on the specific organism class identified. In these
situations, it is up to the applicant/sponsor to seek guidance from the appropriate regulatory
authority.
Finally, conducting EIA studies in accordance with Good Laboratory Practice (GLP) is a regional
requirement. It is preferred that studies should be conducted using methods that allow for a data
audit as may be necessary for some regions. It should be recognized that if studies are not
conducted to GLP, they may not be accepted in some VICH regions.
2.6 Metabolites
In triggering a Phase II assessment, the exposure is based on the total residue approach, as described
in question 11 and 17 of the Phase I document. The fate of chemicals in the environment is
dependent on their chemical/physical properties and degradability. These properties will vary
between the parent compound and the individual excreted metabolites, for example, the latter may
be more water-soluble than the parent compound and may be more mobile and/or more persistent in
the environment.
In general, the data generated at Phase II will be on the parent compound, but the risk assessment
should also consider relevant metabolites. This is especially the case for pro-drugs that are
efficiently metabolized into a single metabolite for which testing may be more appropriate.
Consideration of the excretion data is not initially recommended at Tier A, where a total residue
approach should be taken and a PEC initial should be estimated. It should be assumed that the VMP is
excreted 100% as parent.
If the RQ is ≥1 for one or more tested taxonomic levels, then metabolism/excretion data from the
residues and ADME part of the dossier should be considered as part of the PEC refinement.
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Excreted metabolites representing 10% or more of the administered dose and which do not form
part of biochemical pathways should be added to the active substance to allow the PEC to be
recalculated.
If the RQ is still ≥1 after PEC refinement and testing at Tier B, then guidance should be sought
from the regulatory authority, including whether testing of the major environmentally relevant
metabolites should be considered.
2.7 Special Consideration for Biodegradation Data

At Tier A if the RQ is <1 for all taxonomic levels tested, the assessment should normally stop.
However, for persistent compounds (e.g. DT90 > 1 year in soil based on the annual appication) it is
recommended that the PECinitial be recalculated due to the possibility of accumulation in the
environment.
In case of specific concerns related to the persistence and/or mobility, further investigation of
degradates formed during environmental fate studies may be important. It should be noted that an
individual substance may be both an excreted metabolite and a degradate in the environment. In
both cases guidance should be sought from the regulatory authority.
3 RECOMMENDED STUDIES AT TIER A AND TIER B

Exposure to both the terrestrial and aquatic compartment may be applicable to a particular VMP
depending on its route of environmental introduction. For instance, VMPs administered to
intensively reared animals have the potential to impact terrestrial non-target species directly and
non-target species in surface waters indirectly due to transport in water, including when adsorbed to
soil particles and organic matter. Likewise, VMPs used to treat pasture animals may impact aquatic
as well as terrestrial non-target species. Therefore, there should be a common set of criteria and
studies that will be used when it is determined that testing is recommended. These can be
applicable to all three branches or just two, e.g. intensively reared and pasture animals and are
cross-referenced (as appropriate) in later sections of this document. If there is evidence that there
will be no exposure to a particular compartment (i.e. water, soil/sediment and dung), then it may be
possible to waive studies for that compartment. However, sound scientific evidence should be
presented in the dossier in support of the omission of these studies.
This section summarizes the studies that are recommended at Tier A, and which should be
conducted once it has been determined at Phase I that testing at Phase II is recommended. It also
outlines the process that should be followed to determine whether testing at Tier B may be relevant
and lists the studies recommended at this level.
All testing should be carried out on the parent compound, with the possible exception of VMPs such
as pro-drugs as already discussed in section 2.6.
3.1 Tier A Testing
3.1.1 Tier A Physical-Chemical Properties Studies

Table 1 gives the studies recommended in this area in Tier A for all three Branches. Except where
noted, all studies should be conducted.
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Table 1. Physical-chemical Properties Studies at Tier A
Study Guideline
Water Solubility OECD 105
Dissociation Constants in Water OECD 112
UV-Visible Absorption Spectrum OECD 101
Melting Point/Melting Range OECD 102
Vapour Pressure* OECD 104
n-Octanol/Water Partition Coefficient ** OECD 107 or 117
* Calculation only, though a study is recommended when other physical-chemical properties, e.g. molecular
weight, melting temperature, thermogravimetric analysis suggest that the vapour pressure may exceed 10-5 Pa at
20°C.
** This criterion is not directly applicable to ionisable substances at environmental pH. If appropriate, the
logKow for such substances should be measured on the non-ionised form at environmentally relevant pHs.
3.1.2 Tier A Environmental Fate Studies

Table 2 gives the recommended studies in this area in Tier A for all three branches. The
degradation study should only be performed in soil or aquatic systems, depending on whether the
initial exposure is to the terrestrial or aquatic environment. The photolysis and hydrolysis studies
are optional (see comments under sections 4.2.1.2, 5.2.1.2 and 6.2.1.2) for the three branches.
Table 2. Environmental fate studies at Tier A

Study Guideline
Soil Adsorption/Desorption* OECD 106

Soil Biodegradation (route and rate)** OECD 307
Degradation in aquatic systems** OECD 308
Photolysis (optional) Seek regulatory guidance***
Hydrolysis (optional) OECD 111
*Adsorption/desorption studies should report both the K oc and K d values for a range of soils. Care should be
taken in extrapolating the study results from soil to sediment, especially for substances which are ionized at
environmentally relevant pHs.
** These studies are recommended only for the terrestrial and aquaculture branches, respectively. It may be
appropriate to do the latter studies under saltwater conditions (regulatory guidance should be sought).
*** Draft OECD test guidelines for both aquatic and soil photolysis are in preparation.
3.1.3 Tier A Effects Testing

3.1.3.1 Tier A Aquatic Effects Studies
Table 3 gives the studies and AFs recommended in Tier A for both direct and indirect aquatic
exposures. Testing of three taxonomic levels is recommended. At least one fish, one aquatic
invertebrate and one algal species should be tested and the PNEC estimates for all taxonomic levels
used individually for the RQ calculations.
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VMPs to be used in freshwater should be studied using fresh water species and under freshwater
conditions. Those used in saltwater should be studied using saltwater species and under saltwater
conditions. Only the freshwater studies should be conducted for VMPs used on terrestrial animals.
Species used should be characteristic of the environmental conditions (temperature range
especially) in the region of use.
Table 3. Aquatic effects studies at Tier A
Toxicity
Medium Studies endpoint AF Guideline
EC 50
Freshwater Algal growth 100 OECD 201
inhibition*
EC 50
Freshwater Daphnia 1000 OECD 202
immobilization
Freshwater Fish acute LC 50 1000 OECD 203

toxicity
Saltwater Algal growth EC 50 100 ISO 10253

inhibition
Saltwater Crustacean acute EC 50 1000 ISO 14669

toxicity
Saltwater Fish acute LC 50 1000 Seek regulatory

toxicity guidance
* For substances with anti-microbial activity, some regulatory authorities prefer a blue-green algae rather than a green
algae species be tested.
3.1.3.2 Tier A Terrestrial Effects Studies

Table 4 gives the studies and AFs recommended in Tier A for soil exposures. These are generally
only applicable to VMPs used for terrestrial treatments. All studies should be done and the PNEC
estimates for all taxonomic levels used individually for the RQ calculations. For
endo/ectoparasiticides used in intensively reared animals only, some regulatory authorities may
seek additional information on the toxicity to non-target arthropods (e.g. Collembola).
In general, endo/ectoparasiticidal substances are not considered to be toxic for plants and
microorganisms. Therefore for endo/ectoparasiticides used on pasture animals studies on plants and
microorganisms are only recommended in case the trigger value given in Phase I is exceeded.
Table 4. Terrestrial effects studies at Tier A
Study Toxicity endpoint AF Guideline

Nitrogen Transformation (28 days)* < 25% of control ** OECD 216
Terrestrial plants EC 50 100 OECD 208
Earthworm Subacute/reproduction NOEC 10 OECD 220 /
222
* Studies should be conducted at 1X and 10X the maximum PEC.
** An assessment factor is not relevant to this end point – when the difference in rates of nitrate formation between the
lower treatment (i.e. the maximum PEC) and control is equal to or less than 25% at any sampling time before day 28, the
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VMP can be evaluated as having no long term influence on nitrogen transformation in soils. If this is not the case, the study
should be extended to 100 days at Tier B (see Table 8).
In the specific case of endo/ectoparasiticides used in pasture treatments, the studies listed in Table 5
are also recommended for dung exposures. Regulatory guidance should be sought to determine the
appropriate test guidelines to be used to conduct the toxicity studies for dung fauna. Both dung
beetle larval and dung fly larval data are recommended to assess the effects on dung fauna of
endo/ectoparasiticides excreted in dung. Regulatory guidance should be sought to determine the
appropriate study guidelines to be used to conduct the effects studies for dung fauna. If sound
scientific reasons can be advanced, for example evidence of nil absorption for topicals or extensive
excretion in the urine, then these studies may be waived.
Table 5. Additional effects studies recommended for endo/ectoparasiticides used

for pasture treatments at Tier A
Study Toxicity endpoint AF Guideline

Dung fly larvae EC 50 100 Seek regulatory
guidance*
Dung beetle larvae EC 50 100 Seek regulatory
guidance*
* There are currently no internationally accepted guidelines or processed drafts available for these
studies, but the VICH WG noted the ongoing work in developing standardised studies for dung fly and
dung beetle larvae and their inclusion into the OECD Test Guidelines Program.
Studies for toxicity to vertebrates (e.g. mammals and birds) are not recommended. However, there
may be cases where there is both high toxicity and potential exposure through the food chain and a
consequent risk. An example is risk to birds feeding on the backs of animals that have been treated
with pour-on formulations of endo/ectoparasiticides with potentially high mammalian/avian
toxicity. In these cases, the applicant should consider the mammalian and (if available) avian
toxicity data and seek regulatory guidance as to whether additional data are recommended.
3.1.4 Risk assessment at Tier A

The risk assessment approach that is recommended is to compare the PEC initial based on the total
residue with the PNEC derived for each of the tested taxonomic levels as described above. Where
the RQ for all taxonomic levels is < 1 it should be sufficient to conclude that the VMP does not
pose a risk for the environment, unless based on the persistence of the active substance there is a
potential for it to accumulate in the environment (see section 2.7). Where the RQ is ≥ 1 a risk for
the environment can not be excluded and further assessment is recommended.
3.1.4.1 PEC refinement

The first step should be to refine the PEC initial based on the total residue at Tier A through
consideration of the metabolism/excretion information and the data on biodegradation in
manure/soil/aquatic systems data (see section 2.6 and 2.7). The PEC refined should then be compared
with the PNEC for the affected taxonomic level and a new RQ determined for each. If the RQ is
now <1 for all taxonomic levels, the assessment stops.
If the RQ is still ≥1 for any of the taxonomic levels tested, then the VMP moves to Tier B and
testing for the affected taxonomic level is recommended.
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For pasture treatments if the RQ is ≥1 for dung insects for the PEC dung-initial , then the excretion data
should be examined and the PEC dung-refined used to recalculate the RQ. The PEC dung-initial assumes
that all of the dose is excreted in a single day’s dung. The PEC dung-refined is more realistic as it takes
account of how many days the active substance is excreted in dung and at what concentrations (see
Section 6.2.3.3). If the RQ is still ≥1, further regulatory guidance should be sought.
3.2 Criteria for Tier B Testing

The main criteria for advancing to Tier B is when the RQ is ≥1 or in the case of soil micro-
organisms an effect > 25%. Effects studies at Tier B are only recommended for affected taxonomic
levels. There are two other cases relating to bioaccumulation and sediment invertebrate toxicity
where Tier B testing is recommended.
The logK ow ≥4 is used as a criterion for an assessment of bioaccumulation. This criterion is not
directly applicable to ionisable substances at environmental pH. If appropriate, the logK ow for such
substances should be measured on the non-ionised form at environmentally relevant pHs.
If the RQ for aquatic invertebrate is ≥1 it is recommended to consider the PEC sediment /PNEC sediment
ratio. The PNEC sediment is calculated using equilibrium partitioning. This method uses the
PNEC aquatic invertebrate and the sediment/water partitioning coefficient as input. If the RQ is ≥1, then
testing of sediment organisms is recommended. For substances with a log K ow >5, the RQ is
increased by an extra factor of 10 to take account of possible uptake via ingestion of sediment. If
the RQ is >1, then a study, preferably long-term, with benthic organisms using spiked sediment is
recommended.
3.3 Tier B Testing
3.3.1 Tier B Physical-Chemical Properties Studies

Usually, there are no additional physical-chemical studies recommended in Tier B.
3.3.2 Tier B Environmental Fate Studies

If the logK ow is ≥4, evidence from metabolism/residues/excretion, biodegradation studies and
molecular mass should be considered to see whether there is the potential for bioaccumulation to
occur. If so, then the study listed in Table 6 is recommended to be carried out at Tier B. To assess
the risk for secondary poisoning, the use of a predicted BCF based on QSARs may be considered. If
in doubt, regulatory guidance should be sought.
Table 6. Environmental fate study at Tier B
Study Guideline
Bioconcentration in fish OECD 305
If the BCF is >1000, regulatory guidance should be sought.
3.3.3 Tier B Environmental Effects Studies

3.3.3.1 Tier B Aquatic effects studies
The studies in Table 7 are recommended only for those cases where the RQ for the affected
taxonomic level is ≥1 following use of the PEC refined (see section 3.1.4).
Page 15 of 37
Table 7. Aquatic effects studies at Tier B
Toxicity
Environment Study Endpoint AF Guideline
Freshwater Algae growth inhibition* NOEC 10 OECD 201
Freshwater Daphnia magna NOEC 10 OECD 211

reproduction
Freshwater Fish, early-life stage** NOEC 10 OECD 210
Freshwater Sediment invertebrate NOEC 10 OECD 218,

species toxicity 219***
Saltwater Algae growth inhibition* NOEC 10 ISO 10253
Saltwater Crustacean chronic NOEC 10 Seek regulatory

toxicity or reproduction guidance
Saltwater Fish chronic toxicity NOEC 10 Seek regulatory

guidance
Saltwater Sediment invertebrate NOEC 10 Seek regulatory

species toxicity guidance
* Using the same study and species as in Tier A but the NOEC is used in Tier B.
** Alternative studies for fish: Fish short term toxicity test on embryo and sac-fry stage (OECD TG 212) and Fish
juvenile growth test (OECD TG 215) are not favoured, noting inter alia that the first page of the former suggests why this
may not be the first choice guideline and that OECD TG 210 is preferable.
*** It is suggested that if entry into the environment is through water, OECD TG 219 is used, if exposure is through
sediment or adsorbed to soil in run-off, OECD TG 218 should be used.
If after the Tier B testing the RQ is >1, regulatory guidance should be sought.
3.3.3.2 Tier B Terrestrial effects studies

The studies in Table 8 are recommended only for those cases where the RQ for the affected
taxonomic levels is ≥1 or in the case of soil micro-organisms an effect > 25% following use
of the PEC refined (see above).
Page 16 of 37
Table 8. Terrestrial effects studies at Tier B
Study Endpoint AF Guideline

Nitrogen Transformation (100 days < 25% of * OECD 216
– extension of Tier A study) control
Terrestrial plants growth, more NOEC
10 OECD 208
species**
Earthworm
None
* An assessment factor is not relevant to this end point - when the difference in rates of nitrate formation between the
lower treatment (i.e., the maximum PEC) and control is equal to or less than 25% at any sampling time before day 100,
the VMP can be evaluated as having no long term influence on nitrogen transformation in soils.
** The study should be repeated on two additional species from the most sensitive species category in the Tier A study,
in addition to repeating the study on the most sensitive species.
If after the Tier B testing the RQ is >1 or in the case of soil micro-organisms an effect > 25%,
regulatory guidance should be sought.
For pasture treatments, if the RQ is still ≥1 for dung fauna from the PEC dung-refined , no additional
studies are recommended at Tier B, but regulatory guidance should be sought.
4 AQUACULTURE BRANCH
4.1 Introduction
This section of the Phase II guidance deals with the environmental risk assessments for VMPs used
in aquaculture. A variety of VMPs are administered to aquatic organisms. In many cases these are
added to the organism’s food or directly to their water, or they may be injected directly into the
organism.
Aquaculture practices may vary widely between the VICH regions, but the generic types of
aquaculture facilities are:
• net pens and cages in ocean, coastal and inland areas such as bays, estuaries, fjords, lakes
and lochs;
• raceways, ponds or tanks/baths taking from, and returning water to, streams or rivers;
• raceways, ponds or tanks/baths discharging to a sewage treatment facility; and
• isolated ponds or tanks with limited discharge to a river or sewage treatment facility.
The above give an indication of the spectrum of aquaculture facilities, which range from systems
fully open to essentially closed to the aquatic environment. However, in the majority of cases there
will be dilution of treated water/effluent on release into the environment.
Even with fully open systems during treatment with a VMP the net pen is often raised, e.g. so that
the fish are contained in 2-3 m depth of water and enclosed in a tarpaulin to achieve the required
concentration for a specified time period. At completion of the treatment, the used drug is assumed
to be equally distributed within the reduced volume of water in the net pen. Following removal of
the tarpaulin, the released active substance may initially be distributed evenly within an area of
water around the facility. Eventually more widespread distribution in the environment of the active
Page 17 of 37
substance may occur due to passive diffusion/current movement. In other cases release may be
more direct as no impervious barrier will be in place, or the tarpaulin is placed as a skirt around the
net pen so that the bottom is open.
For systems that are partially closed to the environment, at the end of the VMP treatment release of
effluent to the environment will occur together with other untreated water from the aquaculture
facility. Again there will initially be dilution in receiving waters for a limited distance, followed by
more widespread distribution. In some cases, effluent will pass through a sewage treatment facility,
where there is the opportunity for the active substance to be removed by adsorption/degradation,
prior to discharge to surface waters.
A decision tree/flow diagram is presented in Figure 1 at the end of this section as an overview of the
risk assessment process for various types of VMPs used in aquaculture. The diagram provides a
summary of the text, which is intended as a quick reference to the recommendations. However, the
diagram should always be referred to in conjunction with the main text.
4.2 Tier A
4.2.1 Data recommended in Tier A

If a VMP used in aquaculture has failed to meet Phase I criteria, the following is the minimum
testing data set recommended to be conducted in Tier A.
4.2.1.1 Physical-chemical properties studies

Table 1, Section 3.1.1 gives the studies recommended in Tier A. Except where noted, all studies
should be conducted.
4.2.1.2 Environmental fate studies

Table 2, Section 3.1.2 gives the studies recommended in this area in Tier A. The degradation study
should only be performed in aquatic systems. If initial chemical studies indicate a potential for the
active substance to photolyse or hydrolyse, then photolysis or hydrolysis studies may be conducted.
4.2.1.3 Environmental effects studies

Table 3, Section 3.1.3.1 gives the studies and AFs recommended in Tier A. At least one species
should be studied from each of the three taxonomic levels, i.e. fish, invertebrates and algae in the
relevant medium (fresh or saltwater), and the PNEC to be used for the RQ estimated for each
taxonomic level.
4.2.2 Calculation and comparison of PEC surfacewater

4.2.2.1 Calculation of PEC surfacewater-initial (PEC sw-initial )
The initial risk assessment should be conducted for a PEC sw-initial .
The calculation should be based on:
• the total amount of VMP used in the aquaculture system within the consecutive
administration period for one treatment (see Glossary);
• the volume of the aquatic environment within a defined distance of the treatment area (e.g.
net pens), which is determined by the typical facility for the species and the country/region
where the VMP is to be used;
Page 18 of 37
• the assumption that the active substance is diluted within the system (the extent of which is
dependent on the aquaculture practices and the facility and how it is operated), and then
introduced into the wider environment;
• for a partially closed system, the extent of dilution within the fish farm and how much
further dilution occurs in receiving waters such as running river/stream water when effluent
is discharged from the fish farm; and
• for an open system, the extent of dilution is dependent on the shape, width and depth of the
cultured area and water movement.
4.2.2.2 Comparison of PNEC and PEC sw-initial

At this stage, the PNEC for all taxonomic levels determined during aquatic effects testing should be
compared with the PEC sw-initial . If the RQ is <1 for all taxonomic levels, no further assessment is
recommended. However, if the RQ is ≥1, the PEC sw-initial should be refined, using a number of
mitigations as described in Section 4.2.2.3.
4.2.2.3 Calculation of PEC sw-refined

The PEC sw-initial calculations assume that all of the active substance is retained within the facility
until released, and then is diluted only within a defined distance. The effect of further dispersal in
open systems should be considered. Dispersal may be influenced by external factors such as wind,
currents, tide and the extent of mixing of water as affected by temperature or salinity. The effect of
adsorption onto sediments should be considered. There may also be a number of discrete
applications within the one treatment period, which in open systems would be released as a series of
pulses that will have largely dispersed prior to the next application.
4.2.3 Calculation and comparison of PEC sediment

4.2.3.1 Calculation of PEC sediment
If the RQ for the aquatic invertebrate study is still ≥1 following the calculation of PEC sw-refined , the
PEC sediment should be calculated to compare with the PNEC sediment - (see section 3.2) to indicate
whether an effects study for sediment species is triggered and should be conducted at Tier B. As for
PEC surfacewater , this should initially be carried out at a basic level, and then further refined if
necessary. At the basic level PEC sediment-initial , it should be assumed that partitioning processes
between sediment and water are complete, and that sediment and water are in equilibrium in the
aquatic environment.
4.2.3.2 Calculation of PEC sediment in cases of VMPs added to feed

It is often convenient to administer VMPs in the fish feed, particularly where a treatment has to be
given for several days in succession. In such systems, the VMP may remain associated with waste
feed which usually settles to the sediment under the net pens and for a distance beyond the net pens.
For such VMPs it is also appropriate to calculate the PEC sediment , using the following parameters:
• Percentage administered feed not eaten by fish and subsequently deposited on sediment;
• Total amount of VMP in fish feed;
• Percentage of dose excreted in faeces (in absence of data to the contrary assume this is
100% minus the percentage of uneaten feed);
• Area of sediment directly beneath the net pen(s) and distance beyond net pen(s) in which
uneaten feed and faeces are deposited;
Page 19 of 37
• Depth to which the active substance is distributed in sediment; and

• Density of sediment.
Therefore, the concentration of the active substance in the sediment is a function of the amount
reaching sediment in uneaten feed, the amount reaching sediment in excreted faeces and the
weight/volume of sediment in which the active substance is distributed.
4.2.3.3. Comparison of PNEC and PEC

Once the PEC sediment has been calculated, it should be compared with the PNEC sediment as described
in Section 4.2.3.1 to indicate whether an effects study for sediment species is triggered and should
be conducted at Tier B.
4.3 Tier B
4.3.1 Triggers for testing in Tier B
The criteria for further testing at Tier B are given in Section 3.2.
4.3.2 Data recommended in Tier B


As noted in Section 3.3.2, if the logK ow is ≥4, and following the consideration given in that section,
the bioconcentration study in fish listed in Table 6 is recommended for VMPs used in aquaculture at
Tier B.

If the RQ is still ≥1 for one or more aquatic taxonomic levels, when the PEC sw-refined is compared
with the PNECs calculated for the acute studies conducted in Tier A, chronic testing for that
particular taxonomic level is recommended as indicated in Table 7 of Section 3.3.3.1.
If following refinement, the RQ for an aquatic invertebrate in surface water is ≥1, the
PEC sediment-refined /PNEC sediment should be considered. If RQ is ≥1, a sediment invertebrate effects
study is recommended in Tier B.
4.3.3 Further assessment

If there is still an indication of risk on completion of the Tier B assessment, e.g. for VMPs which
still have an RQ >1 or the BCF ≥ 1000, then the applicant is recommended to discuss their dossier
and proposals for further data or risk mitigation with the regulatory authority.
Page 20 of 37
Figure 1. Decision tree/Flow diagram for VMPs used for aquaculture
Physical-Chemical Studies Environmental Fate Studies Environmental Effects Studies

- UV/VIS absorption spectra Freshwater
- Degradation in aquatic systems
- Melting point/Melting range - Algae growth inhibition
- Photolysis (optional)
- Water solubility - Daphnia immobilization
- Hydrolysis (optional)
- Kow - Fish acute toxicity
- Kd/Koc of soil
- Dissociation constant in water Saltwater
- Vapour pressure (calculation) - Algae growth inhibition
- Crustacean acute toxicity
- Fish acute toxicity
Calculate PECsurfacewater-intial and compare the PEC with each PNEC, calculate RQs for all taxonomic levels tested.
If all RQs are <1 and other criteria are met*, STOP. If not, consider PEC refinement
Refine PECsw-initial and recalculate RQ using PECrefined.

If all RQs are now <1 and other criteria are met*, STOP.
If not, do additional testing only for the relevant species below.
* RQ from PECsw –refined for Environmental effect studies * LogKow ≥ 4, and

aquatic invertebrate ≥ 1. Freshwater
following consideration
Consider given in Section 3.2.2
- Daphnia magna reproduction
PECsediment /PNECsediment. - Fish, early-life stage toxicity
If RQ ≥ 1, do sediment - Algae growth inhibition
study. (use NOEC from Tier A study)
Saltwater
- Crustacean chronic toxicity
- Fish chronic toxicity or reproduction Environmental fate studies
- Algae growth inhibition - Bioconcentration in fish
(use NOEC from Tier A study)
Environmental effect
studies
Freshwater/saltwater If BCF<1000 STOP
If all RQs is now <1 STOP.
-Sediment invertebrate If not, seek regulatory guidance for further studies If ≥1000 seek regulatory
species toxicity or risk management options guidance
Page 21 of 37
5 INTENSIVELY REARED ANIMALS BRANCH
5.1 Introduction
This section of the Phase II guidance deals with the risk assessments for VMPs used in intensively
reared animal systems.
Intensively reared animal systems consist of areas where animals are kept and raised in confined
situations, which may include housed animals or animals kept in feedlots. Producers confine
animals, feed, manure and urine in a relatively small land area (feed-yard). Feed is brought to the
animals rather than the animals only grazing or otherwise seeking feed in pastures, fields, or on
rangelands. Waste is usually disposed of off-site by spreading on adjacent fields. Facilities that
have feedlots with constructed floors, such as solid concrete or metal slots would be considered
intensive rearing practices. If a facility maintains animals in an area without vegetation, including
dirt lots, the facility would also be considered an intensive animal feeding operation. Feedlots with
nominal vegetative growth along the edges while animals are present or during months when
animals are kept elsewhere are also considered to be intensive rearing operations. Beef cattle, dairy
cattle, pigs, chickens, and turkeys are examples of species that may be reared in an intensive
terrestrial system.
risk assessment process for various types of VMPs used in intensively reared animals. The diagram
provides a summary of the text, which is intended as a quick reference to the recommendations.
However, the diagram should always be referred to in conjunction with the main text.
5.2 Tier A

If a VMP used in intensively reared animal systems has failed to meet Phase I criteria, the following
is the minimum testing data set recommended to be conducted in Tier A.


Table 2, Section 3.1.2 gives the studies recommended in Tier A. For VMPs used in intensively
reared animal systems the biodegradation study should be conducted only in soil. If initial chemical
studies indicate a potential for the active substance to photolyse or hydrolyse, then photolysis or
hydrolysis studies may be conducted.

Table 3, Section 3.1.3.1 gives the aquatic effects studies and AFs recommended in Tier A. For
VMPs administered to intensively reared animals at least one species should be tested from each of
the three taxonomic levels e.g. fish, invertebrates and algae, and the PNEC is estimated for each
taxonomic level to be used for the RQ.
Table 4, Section 3.1.3.2 gives the terrestrial effects studies and AFs recommended in Tier A. The
studies provide data on the potential effects to organisms representing three environmental
Page 22 of 37
taxonomic levels in the terrestrial environment that are expected to be exposed, e.g. invertebrates,
plants, and micro-organisms. Again the PNEC estimated for each taxonomic level is to be used for
the RQ.
5.2.2 Calculation and comparison of PEC soil

PECs of residues introduced to soil as a result of use of VMPs in the intensively reared animal
systems are usually based on:
• The total amount of product administered; its dose and frequency of use per animal and
pattern of use within a flock or herd;
• Metabolism in the treated animal, together with the pattern of excretion of parent and
relevant metabolites;
• The manure output of the animal on a weight basis;
• Animal husbandry with respect to the number of animal cycles, length of individual animal
cycles and proportion of year animals are housed;
• Manure storage times in relation to product usage; and
• Manure spreading practices in relation to any restrictions on time of spreading, whether
manure is spread on an area once a year or on several occasions during the year, and legal
or advisory limits to amounts spread.
5.2.2.1 Calculation of PEC soil-initial

In Phase II Tier A the PEC soil-initial is first calculated and used in the risk assessment. As noted in
Section 2.6 this will assume 100% excretion of the administered dose as parent and will have been
calculated as part of the Phase I assessment.
PEC soil-initial should give consideration under spreading practices to the possibility of repeat
applications of manure containing a active substance to the same area of land. As noted in Section
2.7, this will be of particular concern for persistent compounds, where repeat applications over
several years could lead to elevated soil concentrations with consequent effects on soil function and
possibly other environmental impacts.
5.2.2.2 Comparison of PNEC and PEC soil-initial

At Tier A, the PNEC for all the taxonomic levels determined during terrestrial effects testing should
be compared with the PEC soil-initial . If the RQ is <1 for all taxonomic levels tested no further
assessment is recommended. However, if the RQ is ≥1 for one or more taxonomic levels, the worst
case PEC soil-initial should be refined, as described in Section 5.2.2.3, and the RQ recalculated.
5.2.2.3 Calculation of PEC soil-refined

The refinement of PEC soil should occur prior to consideration of conducting any testing in Tier B.
Any refinement should be carried out using appropriate calculations and methods.
PEC soil-initial can be refined by determining the actual composition of the dose excreted by the treated
animal. As noted in Section 2.6, where excretion data are available then the active substance and
relevant metabolites (defined as representing 10% or more of the administered dose and which do
not form part of biochemical pathways) should be added to allow an estimate of the PEC soil-refined .
The PEC may be refined further by several adjustments, including but not limited to the following:
Page 23 of 37
• accounting for any degradation of the active substance during storage of manure before
spreading on fields, as appropriate; and
• by degradation of the parent and relevant metabolites in the field, using the results of the
laboratory soil degradation study from Tier A. Time to mineralization, formation of bound
residue or degradation to substances that are part of biochemical pathways can be used to
refine the PEC in this case.
5.2.3 Calculation and comparison of PEC water

As noted in the introduction to section 3, VMPs administered to intensively reared animals have the
potential to impact non-target species in surface waters indirectly due to transport in water,
including when adsorbed to soils. Therefore, it is appropriate to calculate PECs for both surface
and groundwater.
5.2.3.1 Calculation and comparison of PEC sw-initial

PEC sw-initial will be calculated from any form of indirect entry into surface water. PEC sw-initial is
calculated from the PEC soil-initial .
The factors that affect the likelihood of movement to surface water include the physical and
chemical properties of the active substance, the amount of rainfall and the proportion that is likely
to run off, and soil hydrology.
The PNEC for all tested aquatic taxonomic levels should be determined and compared with the
PEC sw-initial . If the RQ is <1 for all taxonomic levels, no further assessment is recommended.
However, if the RQ is ≥1 for one or more taxonomic levels, the PEC sw-initial should be refined, using
a number of mitigations as described in Section 5.2.2.3, and the RQ recalculated.
5.2.3.2 Calculation of PEC groundwater

The factors important in movement to groundwater include the physical and chemical properties of
the active substance, the amount of soil organic matter, amount of rain, depth to the aquifer or
seasonally saturated layer and preferential flow.
The PEC groundwater should be considered on a regional level for additional testing and/or mitigation
for public health concerns. Groundwater is a natural resource and should not only be assessed with
regards to public health but also to possible harmful effects to the biota of groundwater.
5.3 Tier B
5.3.1 Triggers for further testing in Tier B

5.3.2 Data recommended in Tier B


If the logK ow is ≥4, and following the consideration given in Section 3.3.2, the bioconcentration
study in fish listed in Table 6 is recommended for VMPs at Tier B.
Page 24 of 37

If the RQ is still ≥1 or in case micro-organisms an effect > 25% for one or more taxonomic levels
(both aquatic or terrestrial) when the PEC soil/sw-refined is compared with the results of the studies
conducted in Tier A, testing for that particular taxonomic levels should be carried out as indicated in
Tables 7 and 8 of Section 3.3.3.
study is recommended in Tier B. For calculation PEC sediment see section 4.2.3.1.

still have an RQ >1 or BCF >1000, then the applicant is recommended to discuss their dossier and
proposals for further data or risk mitigation with the regulatory authority.
Page 25 of 37
Figure 2. Decision tree/Flow diagram for VMPs used for intensively-reared animal systems
Physical-Chemical Studies Environmental Fate Studies Environmental Effect Studies

- UV/VIS absorption spectra
- Biodegradation in soil Terrestrial
- Melting point/Melting range
- Kd/Koc of soil - Nitrogen transformation*
- Water solubility
- Photolysis (optional) - Terrestrial plants growth
- Kow
- Hydrolysis (optional) - Earthworm subacute/reproduction
- Dissociation constant in water
- Vapour pressure (calculation) Aquatic
- Algae growth inhibition
- Daphnia immobilization
Calculate the PECsintial and compare the PECs with each PNEC, calculate RQs for all taxonomic levels tested.
If all RQs are <1 and other criteria are met*, STOP. If not, consider PEC refinement
Refine PECinitial for compartment(s) of concern and recalculate RQ using PECrefined.

If all RQs are <1 and other criteria are met*, STOP.
If not, do additional testing from lists below only for the relevant species below.

aquatic invertebrate ≥ 1. following consideration
Consider Terrestrial given in Section 3.2.2
PECsediment /PNECaqinvert. - Nitrogen transformation test (100 days)
If RQ ≥ 1, do sediment - Terrestrial plants growth test (more species)
study Aquatic
- Daphnia reproduction
- Fish early-life stage Environmental fate studies
- Algal growth inhibition - Bioconcentration in fish
(use NOEC of Tier A test)
studies
Freshwater If all RQs is now <1 and other criteria are met STOP. If BCF<1000 STOP
-Sediment invertebrate If not, seek regulatory guidance for further studies or
species toxicity risk management options If ≥1000 seek
regulatory guidance
Page 26 of 37
6 PASTURE ANIMALS BRANCH
6.1 Introduction
This section of the Phase II guidance deals with the environmental risk assessment for VMPs used
in animals kept at pasture.
Pasture is defined as land covered with grass or herbage and grazed by or suitable for grazing by
livestock. Pasture animals are those livestock reared for part or all of the year on grassland, and
refers only to the time spent at pasture. Excretion occurs directly onto the pasture or onto other
habitats within the grazed area. This is in contrast to intensive systems such as feedlots where
manure is collected and later spread onto agricultural or grassland. At pasture, grazing provides the
primary source of food for livestock.
The types of pasture where animals are grazed will vary according to their situation within a region,
for instance in different parts of the EU, and also between regions, e.g. there will be differences
between Japan and Australia. The number of animals that can be maintained on an area of land will
be limited; and the number of animals/hectare is referred to as the stocking density that will vary
both within and between regions.
For animals reared on pasture, there are specific concerns for certain types of products related to
their direct entry to the aquatic environment. There are also some specific areas of environmental
concern relating to endo/ectoparasiticides used in animals at pasture and both of these are described
in this guidance.
risk assessment process for various types of VMPs used in pasture animals. The diagram provides a
summary of the text, which is intended as a quick reference to the recommendations. However, the
diagram should always be referred to in conjunction with the main text.
6.2 Tier A

If a VMP used on pasture animals has failed to meet Phase I criteria, the following is the minimum
testing data set recommended to be conducted in Tier A.


Table 2, Section 3.1.2 gives the studies recommended in this area in Tier A. For pasture animal
VMPs the biodegradation study should be conducted only in soil. If initial chemical studies
indicate a potential for the active substance to photolyse or hydrolyse, then photolysis or hydrolysis
studies may be conducted.

Table 3, Section 3.1.3.1 gives the aquatic effects studies and AFs recommended in Tier A. For
VMPs administered to pasture animals at least one species should be tested from each of the three
Page 27 of 37
taxonomic levels i.e. fish, invertebrates and algae, and the PNEC estimated for each taxonomic
level is to be used for the RQ calculations.
Table 4, Section 3.1.3.2 gives the terrestrial effects studies and AFs recommended in Tier A. The
studies provide data on the potential effects to organisms representing three environmental
taxonomic levels in the terrestrial environment that are expected to be exposed, e.g. invertebrates,
plants, and micro-organisms. However, for endo/ectoparasiticides used on pasture animals studies
on plants and microorganisms are usually recommended only in the case the trigger value given in
Phase I is exceeded. If data are available to show a concern for these taxonomic levels the studies
are recommended. Again the PNEC estimated for each taxonomic level is to be used for the RQ
calculations.
Both dung beetle larval and dung fly larval data are recommended to assess the effects on dung
fauna of endo/ectoparasiticides excreted in dung. Regulatory guidance should be sought on the
appropriate study guidelines to use to assess toxicity to dung fauna. An earthworm study, listed in
Table 4, is also recommended in regions where dung is colonised by earthworms.
6.2.2 Calculation and comparison of PEC soil

VMPs may be used on animals that are kept at pasture, rather than being housed or kept in feedlots.
Consequently, any excretion of the active substance in urine or faeces will occur at pasture, rather
than being collected, stored and spread onto land as manure. The proportion of the year livestock
spend on pasture, in relation to the timing of treatment, is an important consideration when
calculating the range of PEC values.
6.2.2.1 Calculation of PEC soil-initial

At Tier A, an initial calculation of PEC soil-initial is recommended for all VMPs used in pasture
animals, including topical products that are absorbed and excreted. Even though a later calculation
will be done for PEC dung-initial , at this stage the worst case calculation of PEC soil-initial should take
account of active substance excreted in both faeces and urine. While in general, there will be
excretion data available to determine the percentage of the administered dose of VMP excreted, and
the relative contribution of parent and metabolites, initially it should be assumed that 100% of the
administered dose is excreted onto pasture.
The PEC soil-initial is based on:
• 100% excretion of the administered dose;
• an assumption regarding depth of soil to which residue is distributed;
• livestock stocking density; and
• an even distribution of the active substance across the field.
6.2.2.2 Comparison of PNEC with PEC soil-initial

At this stage, the PNECs for all taxonomic levels determined from terrestrial effects testing should
be compared with the PEC soil-initial . If the RQ is <1 for all taxonomic levels tested no further
assessment is recommended. However, if the RQ is ≥1, the PEC soil-initial should be refined, using a
number of mitigations as described in Section 6.2.2.3, and the RQ recalculated.
6.2.2.3 Calculation of PEC soil-refined

The refinement of PEC soil should occur prior to consideration of conducting any testing in Tier B.
Any refinement should be carried out using appropriate calculations and methods. Further
Page 28 of 37
refinement of PEC soil can be done as described in Section 5.2.2.3 of the Intensively Reared Animals
Branch.
6.2.3 Calculation and comparison of PEC dung

6.2.3.1 Calculation of PEC dung-initial
Some VMPs are excreted predominantly in the dung rather than in urine. Where such VMPs
remain associated with the dung they are unlikely to be distributed in the soil initially, though there
may be subsequent incorporation into soil by dung/soil fauna or by leaching.
For active substances excreted predominantly in dung, the PEC dung-initial should be estimated. This is
the maximum concentration of the active substance in dung, and initially it should be assumed that
there are no excretion data of the active substance in dung. Therefore, the PEC dung-initial should be
calculated assuming that 100% of the dose is excreted in dung on a single day.
This is relevant in particular to endoparasiticides and ectoparasiticides that will be excreted at
pasture following oral, parenteral or topical administration. For these products, the PEC soil-initial
should also be estimated. However, there is also a need to estimate the concentration in dung as
these products have the potential to affect dung fauna.
6.2.3.2 Comparison of PNEC with PEC dung-initial

At this stage, the PNECs derived for dung fly, dung beetles and if applicable for earthworms should
be compared with the PEC dung-initial . If the RQ is <1 for all taxonomic levels tested no further
assessment is recommended. However, if the RQ is ≥1, the PEC dung-initial should be refined, as
described in Section 6.2.3.3, and the RQ recalculated.
6.2.3.3 Calculation of PEC dung-refined

In Tier B, the concentration in dung, PEC dung , is not expressed as a single value. Excretion studies
may be used to produce more realistic estimates of the PEC dung . Data should be obtained on the
concentrations of active substance in fresh dung excreted by treated animals. Dung concentrations
should be measured by an appropriate method and for a period adequate to determine the
concentrations of ecotoxicological significance.
The maximum PEC in dung excreted at each time point is compared to the PNEC for dung fauna.
An assessment can then be made of the time period after treatment during which dung is toxic to
dung fauna.
6.2.4 Calculation and comparison of PEC water

6.2.4.1 Surface water and groundwater
VMPs administered to pasture animals have the potential to impact non-target species in surface
waters indirectly due to transport in water, including when adsorbed to soils. Therefore it is
appropriate to calculate PECs for both surface and groundwater (see Section 5.2.3 of this guidance).
However, the PEC groundwater should be considered at a regional level.
In addition there are other routes of exposure to the aquatic environment that are specific to animals
reared at pasture. These are described in Section 6.2.4.2 and should also be referred to.
6.2.4.2 Aquatic Exposure Scenarios

There are a number of ways that contamination of the aquatic environment may occur and more
than one of the scenarios below may be relevant to an individual product. Therefore it may be
Page 29 of 37
appropriate to add the PEC values from the different routes of exposure to arrive at a PEC total .
Alternatively the different routes of exposure may mean that contamination of surface water occurs
over a longer period of time. These factors should be considered when estimating the PEC sw-initial .
An initial risk assessment can be conducted at Tier A using the PEC sw-initial based on the
concentration estimated in the scenarios below.
6.2.4.2.1 Direct excretion of active substance into surface waters from pasture animals
This is relevant in pasture situations where livestock have direct access to surface waters as a source
of drinking water. In addition, it is only relevant to those livestock species, e.g. cattle, that spend
time standing in the water.
6.2.4.2.2 Contamination of hard-standing areas during application of topical

ectoparasiticides, leading to indirect exposure of the aquatic environment
through run-off from these surfaces following rainfall
This exposure scenario applies in situations where animals are gathered together in a specific area
of the farm for application of topical ectoparasiticides. This may be an area of pasture, an area of
bare ground, or an area of concrete. Such areas will become contaminated with VMPs as a result of
mixing concentrate, splashing during administration, or from excess liquid draining from animals.
During subsequent rainfall events there is potential for surface run-off of the active substance from
this area to surrounding soil and nearby surface waters.
6.2.4.2.3 Entry of animals treated with high volume ectoparasiticides into surface waters
leading to direct exposure of the aquatic environment
Animals treated with high volume VMPs include those that have been dipped, jetted or showered.
After a period of time to allow excess liquid to drain off, treated animals will be returned to pasture.
If they enter surface waters before the active substance has dried and adsorbed onto the greasy part
of the fleece or hide, it will be readily lost into surface waters where the treated part of the body
comes into direct contact with water. This will generally involve shallow surface waters and it may
only be the legs, and possibly also the underbelly, that come into contact with water.
In general, animals that have been treated with a pour-on product (i.e., low volume) will not
contaminate surface waters in this way, due to the low volumes used and the area of the animal to
which the product is applied.
6.2.4.2.4 Use and disposal of sheep dip

Disposal of dilute dip to vegetated areas will lead to exposure of the soil and associated vegetation,
as well as groundwater. High volume disposal of ectoparasiticides to land represents a potential
impact in the environment and risk management may be important 1 to prevent this impact. Where
this practice is allowed, data should enable an assessment of the risk to the environment to be
performed, as part of the authorization process for these VMPs. These situations should be
addressed by the applicant in consultation with the appropriate regulatory authority on a case-by-
case basis.
1 This guidance document, developed under the VICH process, has been revised to conform to FDA’s good guidance
practices regulation (21 CFR 10.115).
Page 30 of 37
6.2.4.2.5 Sheep wool processing effluent

This issue is a concern for certain regions, but not for all regions that are party to VICH. Therefore,
this issue will not form part of this guidance document. Applicants should approach the relevant
regulatory authority for guidance.
6.2.4.3 Comparison of PNEC with PEC sw-initial

The PNECs for all the taxonomic levels determined during the aquatic effects testing should be
compared with the PEC sw-initial . If the RQ is <1 no further assessment is recommended. However, if
the RQ is ≥1, the PEC sw-initial should be refined, as described in Section 6.2.4.4, and the RQ
recalculated.
6.2.4.4 Calculation of PEC sw-initial-refined

For PEC sw-initial it would be more realistic to assume that there is dilution and dispersion following
entry into surface waters and there is the option to revise the PEC sw-refined in this way if the RQ are
>1 for any aquatic taxonomic level. This should take account of the volume of the receiving water
and the water flow-rate to estimate the extent of dispersion and dilution. The resulting PEC sw-refined
will be lower, due to degradation, dilution, adsorption and dispersion, but will cover a larger area.
Estimates should be made of the area affected and the resulting concentration. These estimates will
tend to be region specific and advice may be sought from the regulatory authority. However, they
are only empirical models at this stage, based on simple estimates, which can be refined later if
necessary.
6.3 Tier B
6.3.1 Triggers for further testing in Tier B

6.3.2 Data recommended for Tier B


If the logK ow is ≥4, and following the consideration given in Section 3.3.2, the bioconcentration
study in fish listed in Table 6 is recommended for VMPs at Tier B.

If following refinement of the PECs the RQ is still ≥1 for one or more taxonomic levels (both
aquatic or standard terrestrial) when the PEC soil/sw-refined is compared with the PNEC derived from
Tier A or in case of micro-organisms an effect > 25%, additional testing for the particular
taxonomic levels should be carried out as indicated in Tables 7 and 8 of Section 3.3.3.
For the studies on dung fauna, if the RQs at Tier B, i.e. comparison of PEC dung-refined and PNEC, are
still ≥1 for one or more taxonomic levels, then further testing should be conducted to determine the
risk. Regulatory guidance should be sought on appropriate studies.
Page 31 of 37
study is recommended in Tier B. For calculation PEC sediment see section 4.2.3.1.

still have an RQ >1 or BCF ≥ 1000, then the applicant is recommended to discuss their dossier and
proposals for further data or risk mitigation with the regulatory authority.
Page 32 of 37
Figure 3. Decision tree/Flow diagram for VMPs used for pasture animals
Physical-Chemical Studies Environmental Fate Studies Environmental Effect Studies

- UV/VIS absorption spectra
- Biodegradation in soil Terrestrial
- Melting point/Melting range
- Kd/Koc of soil - Nitrogen transformation*
- Water solubility
- Photolysis (optional) - Terrestrial plants growth
- Kow
- Hydrolysis (optional) - Earthworm subacute/reproduction
- Dissociation constant in water
- Vapour pressure (calculation)
Aquatic
Dung fly and beetle tests - for - Algae growth inhibition
endo/ectoparasiticides only - Daphnia immobilization
Calculate PECsintial and compare the PECs with each PNEC, calculate RQs for all taxonomic levels tested.
If all RQs are <1 and all other criteria are met*, STOP. If not, consider PEC refinement
If RQ ≥1 for one or more taxonomic levels , refine PECinitial for compartment(s) of concern and
recalculate RQ using PECrefined. If all RQs are now <1 and all other are criteria met*, STOP.
If not, do additional testing from lists below only for the relevant species.
For effects on dung insects seek regulatory guidance.

aquatic invertebrate ≥ 1. following consideration
Consider: Terrestrial given in Section 3.2.2
PECsediment /PNECsediment. - Nitrogen transformation test (100 days)
If RQ ≥ 1, do sediment test - Terrestrial plants growth test (more species)
Aquatic
- Daphnia reproduction Environmental fate studies
- Fish early-life stage
- Algal growth inhibition - Bioconcentration in fish
(use NOEC of Tier A test)
studies
Freshwater If all RQs are <1and other criteria are met STOP. If BCF<1000 STOP
- Sediment invertebrate If not, seek regulatory guidance for further studies
species toxicity or risk management options If ≥1000 seek regulatory
guidance
Page 33 of 37
7 GLOSSARY (DEFINITIONS OF TERMS)
Active substance = parent and/or its metabolites

ADME = Absorption, Distribution, Metabolism, Excretion
BCF = Bioconcentration Factor
DT 90 = Time to degradation of 90% of original concentration of the compound in
the tested soils.
EC 50 = The concentration of a test substance which results in 50% of the test
animals being adversely affected, i.e., both mortality and sub-lethal effects.
Kd = Sorption/desorption coefficient
K oc = Sorption/desorption coefficient, normalized to organic carbon content
K ow = n-Octanol/water partitioning coefficient
LC50 = The concentration of a test substance which results in a 50% mortality of
the test species.
NOEC = No-observed effect concentration, i.e., the test concentration at which no
adverse effect occurs.
OECD = Organization for Economic Co-operation and Development
One treatment = is considered to be administration of the VMP in accordance with the
proposed marketing authorisation/registration, taking into account
indication, amount administered and method of administration. A treatment
can consist of multiple applications (e.g. once a day for seven consecutive
days).
QSAR = Quantitative Structure Activity Relationship
Page 34 of 37
8 OECD/ISO TEST GUIDELINES FOR RECOMMENDED STUDIES
OECD Guidelines for the Testing of Chemicals

(http://www.oecd.org/en/home/0,,en-home-524-nodirectorate-no-no-no-8,00.html)
Section 1 – OECD Physical-Chemical Properties

ADOPTED TEST GUIDELINES
TG No. Title
101 UV-VIS Absorption Spectra (Original Guideline, adopted 12th May 1981)
102 Melting Point/Melting Range (Updated Guideline, adopted 27th July 1995)
104 Vapour Pressure (Updated Guideline, adopted 27th July 1995)
105 Water Solubility (Updated Guideline, adopted 27th July 1995)
106 Adsorption/Desorption Using a Batch Equilibrium Method (Updated Guideline,
adopted 21st January 2000)
107 Partition Coefficient (n-octanol/water): Shake Flask Method (Updated Guideline,
adopted 27th July 1995)
111 Hydrolysis as a Function of pH (Original Guideline, adopted 12th May 1981)
112 Dissociation Constants in Water (Original Guideline, adopted 12th May 1981)
117 Partition Coefficient (n-octanol/water), HPLC Method (updated Guideline, adopted 1st
February 2004)
Page 35 of 37
Section 2 – OECD Effects on Biotic Systems

TG No. Title
201 Alga, Growth Inhibition Test (Updated Guideline, adopted 7 June 1984)
202 Daphnia sp. Acute Immobilisation Test and Reproduction Test (updated Guideline,
adopted 1st February 2004)
203 Fish, Acute Toxicity Test (Updated Guideline, adopted 17th July 1992)
208 Terrestrial Plants, Growth Test (Original Guideline, adopted 4th April 1984)
210 Fish, Early-Life Stage Toxicity Test (Original Guideline, adopted 17th July 1992)
211 Daphnia magna Reproduction Test (Original Guideline, adopted 21st September
1998)
216 Soil Microorganisms, Nitrogen Transformation Test (Original Guideline, adopted 21st
January 2000)
218 Sediment Water Chironomid Toxicity Test Using Spiked Sediment (Original
Guideline, adopted 1st February 2004)
219 Sediment Water Chironomid Toxicity Test Using Spiked Water (Original Guideline,
220 Enchytraeidae Reproduction Test (Original Guideline, adopted 1st February 2004)
222 Earthworm Reproduction Test (Eisenia fetida/Eisenia Andrei) (Original Guideline,
Section 3 – OECD Degradation and Accumulation

TG No. Title
305 Bioconcentration: Flow-through Fish Test (Updated Guideline, adopted 14th June
1996)
307 Aerobic and Anaerobic Transformation in Soil (Original Guideline, adopted 24 April
2002)
308 Aerobic and Anaerobic Transformation in Aquatic Sediment Systems (Original
Guideline, adopted 24 April 2002)
Page 36 of 37
Section 4 – ISO Guidelines

ISO No. Title
10253 Marine algae growth inhibition test with Skeletonema costatum and Phaeodactylum
tricornutum
14669 Determination of acute lethal toxicity to marine copepods (Copepoda, Crustacea)
Page 37 of 37

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166

Guidance for Industry

ENVIRONMENTAL IMPACT ASSESSMENTS (EIA’s) FOR

U.S. Department of Health and Human Services

VICH GL 38 (ECOTOXICITY PHASE II)

E NVIRONMENTAL I MPACT A SSESSMENT FOR

Recommended for Adoption

4 AQUACULTURE BRANCH ............................................................................... 17

5.2.3 ...... Calculation and comparison of PEC water .............................................24

6.3.2.1 Physical-chemical properties studies ........................................................ 31

ENVIRONMENTAL IMPACT ASSESSMENT FOR VETERINARY

1.1 Purpose of this Guidance Document

2.1 Protection Goals

2.2 General Description and Use of Phase II

2.3 Exposure of VMPs to the Environment

2.4 Risk Quotient (RQ) Approach

2.5 Test Guidelines

2.7 Special Consideration for Biodegradation Data

3 RECOMMENDED STUDIES AT TIER A AND TIER B

3.1 Tier A Testing

3.1.1 Tier A Physical-Chemical Properties Studies

Table 1. Physical-chemical Properties Studies at Tier A

3.1.2 Tier A Environmental Fate Studies

Table 2. Environmental fate studies at Tier A

Soil Adsorption/Desorption* OECD 106

3.1.3 Tier A Effects Testing

Table 3. Aquatic effects studies at Tier A

Freshwater Fish acute LC 50 1000 OECD 203

Saltwater Algal growth EC 50 100 ISO 10253

Saltwater Crustacean acute EC 50 1000 ISO 14669

Saltwater Fish acute LC 50 1000 Seek regulatory

3.1.3.2 Tier A Terrestrial Effects Studies

Table 4. Terrestrial effects studies at Tier A

Study Toxicity endpoint AF Guideline

Table 5. Additional effects studies recommended for endo/ectoparasiticides used

Study Toxicity endpoint AF Guideline

3.1.4 Risk assessment at Tier A

3.1.4.1 PEC refinement

3.2 Criteria for Tier B Testing

3.3 Tier B Testing

3.3.1 Tier B Physical-Chemical Properties Studies

3.3.2 Tier B Environmental Fate Studies

Table 6. Environmental fate study at Tier B

3.3.3 Tier B Environmental Effects Studies

Table 7. Aquatic effects studies at Tier B

Freshwater Algae growth inhibition* NOEC 10 OECD 201

Freshwater Daphnia magna NOEC 10 OECD 211

Freshwater Fish, early-life stage** NOEC 10 OECD 210

Freshwater Sediment invertebrate NOEC 10 OECD 218,

Saltwater Algae growth inhibition* NOEC 10 ISO 10253

Saltwater Crustacean chronic NOEC 10 Seek regulatory

Saltwater Fish chronic toxicity NOEC 10 Seek regulatory

Saltwater Sediment invertebrate NOEC 10 Seek regulatory

3.3.3.2 Tier B Terrestrial effects studies

Table 8. Terrestrial effects studies at Tier B

Study Endpoint AF Guideline

4.2.1 Data recommended in Tier A

4.2.1.1 Physical-chemical properties studies

4.2.1.2 Environmental fate studies

4.2.1.3 Environmental effects studies

4.2.2 Calculation and comparison of PEC surfacewater

4.2.2.2 Comparison of PNEC and PEC sw-initial

4.2.2.3 Calculation of PEC sw-refined

4.2.3 Calculation and comparison of PEC sediment